An electrochemically driven, nickel-catalyzed reductive coupling of N-hydroxyphthalimide esters with aryl halides is reported. The reaction proceeds under mild conditions in a divided electrochemical cell and employs a tertiary amine as the reductant. This decarboxylative C(sp3)–C(sp2) bond-forming transformation exhibits excellent substrate generality and functional group compatibility. An operationally simple continuous-flow version of this transformation using a commercial electrochemical flow reactor represents a robust and scalable synthesis of value added coupling process.

Antibody-drug conjugates (ADC) target cytotoxic drugs to antigen-positive cells for treating cancer. After internalization, ADCs with noncleavable linkers are catabolized to amino acidlinker-warheads within the lysosome, which then enter the cytoplasm by an unknown mechanism. We hypothesized that a lysosomal transporter was responsible for delivering noncleavable ADC catabolites into the cytoplasm. To identify candidate transporters, we performed a phenotypic shRNA screen with an anti-CD70 maytansine-based ADC. This screen revealed the lysosomal membrane protein SLC46A3, the genetic attenuation of which inhibited the potency of multiple noncleavable antibodymaytansine ADCs, including ado-trastuzumab emtansine. In contrast, the potencies of noncleavable ADCs carrying the structurally distinct monomethyl auristatin F were unaffected by SLC46A3 attenuation. Structure-activity experiments suggested that maytansine is a substrate for SLC46A3. Notably, SLC46A3 silencing led to relative increases in catabolite concentrations in the lysosome. Taken together, our results establish SLC46A3 as a direct transporter of maytansine-based catabolites from the lysosome to the cytoplasm, prompting further investigation of SLC46A3 as a predictive response marker in breast cancer specimens. Cancer Res; 75(24); 5329-40. Ó2015 AACR.

A general Rh(III)-catalyzed synthesis of naphthyridinone derivatives is described. It relies on a double-activation and directing approach leveraging nicotinamide N-oxides as substrates. In general, high yields and selectivities can be achieved using low catalyst loadings and mild conditions (room temperature) in the couplings with alkynes, while alkenes require slightly more elevated temperatures.

A practical, efficient synthesis of 1, a hepatitis C virus RNA replication inhibitor, is described. Starting with the inexpensive diacetone glucose, the 12-step synthesis features a novel stereoselective rearrangement to prepare the key crystalline furanose diol intermediate. This is followed by a highly selective glycosidation to couple the C-2 branched furanose epoxide with deazapurine.

An efficient asymmetric synthesis of a selective estrogen receptor modulator (SERM) that has a dihydrobenzoxathiin core structure bearing two stereogenic centers is reported. The stereogenic centers were established by an unprecedented chiral sulfoxide-directed stereospecific reduction of an ␣,␤-unsaturated sulfoxide to the saturated sulfide in one step. Studies to elucidate the mechanism for this reduction are reported. Highly efficient Cu(I)-mediated ether formation was used to install the ether side chain, and selective debenzylation conditions were developed to remove the benzyl protecting groups on the phenols. E strogen receptors (ERs) are members of the steroid hormone nuclear receptor superfamily. They are ligand-dependent transcription factors that bind to specific DNA sequences and regulate gene expression. There are two known members of the estrogen receptor family, ER␣ and ER␤, encoded by distinct genes. ER modulators are potentially useful agents for treatment or prevention of a variety of conditions related to estrogen functions, including bone loss, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of low-density lipoprotein cholesterol, cardiovascular disease, obesity, incontinence, and cancer (refs. 1-4 and references cited in ref. 4). SERMs are ER ligands that act like estrogens in some tissues, but block estrogen action in others. Thus, SERMs may exhibit an agonistic or antagonistic activity, depending on the context in which their activity is examined. Fig. 1) is a potent ER␣ SERM being evaluated as part of the selective ER antagonist program at Merck (1-4). Although there are several methods for the synthesis of the core cis-2,3-disubstituted-dihydrobenzoxathiin, the asymmetric synthesis of these compounds has not been reported (1-7). Herein, we report an enantioselective synthesis of 1. Experimental ProceduresGeneral. Chemicals were used as received from commercial sources unless otherwise noted. NMR data were collected on Bruker Avance NMR spectrometers. Chemical shifts are reported in ppm downfield from tetramethylsilane. HPLC purity data are reported as area percentage of the desired peak from the total peaks. HPLC conditions are listed in supporting information, which is published on the PNAS web site. High-resolution mass spectrometer (HRMS) data were collected on a Micromass API US Ultima quadrupole time-of-flight (QTOF) mass spectrometer. Vinyl Sulfide 6.A 100-liter round-bottom flask was charged with ketone 7 (8.01 kg, 12.2 mol) and 48 liters of acetonitrile followed by phenylphosphonic dichloride (2.50 kg, 12.9 mol). The flask was fitted with a reflux condenser with off-gases vented through a caustic scrubber, and the reaction mixture was heated to reflux (75°C). After about 2 h, HPLC assay showed Ͼ99% conversion. The reaction mixture was concentrated under reduced pressure at 20-50°C to 28 liters. Diisopropylethylamine (786 g, 6.08 mol) was added, followed by 28 liters of denatured ethanol (denatured with 0.5% toluene). The solution was ...